Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the signature injury of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts. Repetitive mTBI characteristic of troops deployed to Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF), may have devastating personal, professional and domestic consequences. Impairment of memory and concentration, increased anxiety, irritability and mood instability, and sleep disturbance interfere with job and family relationships, producing substantial disability. In addition to these immediate consequences of mTBI, blast trauma damage to brain tissue and/or subsequent brain reparative effects may initiate processes leading to neurodegeneration and dementia. This proposal will apply advanced functional and structural neuroimaging and cerebrospinal fluid (CSF) biomarkers to address the following questions: 1) Are there objective neuroimaging and CSF biomarkers that: a) characterize the behavioral phenotype of blast-induced mTBI; and b) distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD)? 2) Is there long-term cognitive impairment in repetitive blast mTBI and, if so, is cognitive impairment associated with CSF biomarkers of and genetic risk factors for neurodegenerative dementia? The term mTBI here is used to denote a syndrome of persistent postconcussive symptoms ([PCS] cognitive, behavioral, and somatic) that continue to be expressed months and years after blast concussion events that produce mTBI. Our preliminary neuroimaging results demonstrate previously unrecognized structural and functional abnormalities independent of comorbid PTSD in OIF/OEF Veterans with mTBI and persistent PCS. Specific Objective 1: To characterize the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of blast trauma repetitive mild traumatic brain injury (mTBI) in OIF/OEF Veterans with PCS. Specific Objective 2: To determine if OIF/OEF Veterans with repetitive mTBI with persistent PCS express CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Objective 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on both clinical characteristics, and neuroimaging and CSF biomarkers in OIF/OEF Veterans with repetitive mTBI and persistent PCS. This proposal addresses the RR&D priority areas of Validation and Refinement of Diagnostic Imaging Technology and Innovative Approaches to Late or Long-Term Consequences of TBI. VHA faces a huge burden of providing primary medical, rehabilitative, mental health and long term care to this vulnerable population. Identification of objective neuroimaging and CSF biomarkers of mTBI and clarification of the long- term risks of neurodegenerative dementias in mTBI will: 1) improve diagnosis of mTBI, 2) provide targets for improving Veterans' health care; and 3) allow appropriate allocation of limited health care, compensation and pension, and social resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. Within 24 months, the project will yield tools for objective biomarker diagnosis of mTBI. Within 4 years, results from the proposed project will form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.